Reshaping the glycocalyx: the SULF extracellular endosulfatases as molecular editors of heparan Sulfate

Heparan sulfate proteoglycans are central modulators of cell-cell communication, largely through the information encoded in their sulfation patterns. Among extracellular regulators of this 'heparan sulfate code', the endosulfatases SULF1 and SULF2 have emerged as unique enzymes with the capacity to selectively remove 6-O-sulfate groups from heparan sulfate (HS) glucosamine residues. This activity distinguishes them from canonical lysosomal sulfatases and positions them as critical editors of HS from the extracellular matrix and cell-surface. Recent biochemical studies have highlighted their distinctive domain organization, extensive post-translational modifications, and finely tuned substrate specificity, revealing that 6-O-desulfation is a non-random, highly regulated process. Functionally, SULFs influence major signaling pathways and thereby participate in diverse biological processes, such as development, tissue homeostasis, injury repair, inflammation, and tumor progression. Accumulating evidence also implicates SULF1 and SULF2 in disease pathogenesis and highlights them as promising, yet underexplored, therapeutic targets. In the present review, we provide an updated perspective on SULF biology, emphasizing recent advances in functional characterization, their roles as extracellular 'code editors', and the therapeutic opportunities that may arise from targeting their activity. We also address several key questions that remain unresolved and that are needed to understand this complex mechanism of regulation.